1. Field of the Invention and Prior Art
The present invention relates to novel prolonged release formulations or compositions, e.g., tablet, granule, lozenge, capsule, or like formulations, containing a gel-forming dietary fiber and a drug or other active therapeutic agent plus certain essential disintegrants.
Many drugs and vitamins must be released in a uniform and/or continuous manner over a period of time. Water-soluble vitamins, for example, unless placed into a time-release form, are almost immediately released into the blood stream once they dissolve in the stomach. Aspirin is frequently coated to minimize gastric upset and release the drug over a period of time. Sustained-release dosage forms also avoid the necessity of frequent administration of the drug while, at the same time, achieving a desired blood level of active ingredient.
Various cellulose derivatives have been used to provide rapid disintegration of tablets, such as in U.S. Pat. No. 3,266,992, which describes the use of methylcellulose, sodium carboxymethylcellulose and hydroxyethylcellulose for such purpose. However, in contrast, hydroxypropylmethylcellulose in enteric coatings has been disclosed in U.S. Pat. No. 2,887,440 to prevent disintegration of a tablet core and delay release of the active ingredients.
U.S. Pat. No. 3,870,790 discloses a method of preparing a long-acting buccal composition for admini-stering a therapeutic agent using an effective amount of hydroxypropylmethylcellulose which has been subjected to controlled humidity. Other processes for treating cellulose derivatives are described in U.S. Pat. Nos. 4,226,849, 4,357,469, 4,369,172, 4,389,393, 4,540,566, 4,795,327, and 4,849,229, the treated cellulose derivatives then being used in a solid drug dosage unit form to produce a controlled and prolonged release pattern of a drug upon administration thereof.
For purposes of definition in this Specification, the term "dietary fiber" is defined as "remnants of plant cells resistant to hydrolysis by the alimentary enzymes of man, the group of substances that remain in the ileum but are partly hydrolyzed by bacteria in the colon", according to JAMA 262, No. 4, 542,546 (Jul. 28, 1989) in the Council Report entitled "Dietary Fiber and Health", at page 542. This article, moreover, gives considerable information as to what constitutes a "dietary fiber" and is accordingly incorporated herein by reference.
Gel-forming dietary fibers include mucilages, plant gums, pectins or pectic substances, and lignin, all of which are endogenous compounds of plant materials which are resistant to digestion by enzymes in the monogastric stomach or small intestine. Chemically, nearly all of these plant materials are carbohydrates composed of repeating monosaccharide (sugar) units. Disaccharides have two sugar units, oligosaccharides three to twelve, and polysaccharides may contain a million or more. The water-soluble fractions of these substances form gels in the stomach and intestinal tract and are known to lower serum cholesterol.
Gums and mucilages have no common structure but are polysaccharides containing several sugars with alternating monomer structures and may or may not contain uranic acids. There are many gums found in plants and cereal grains. Guar and locust bean gums are galactomannans, whereas gum arabic is an acidic polymer of galactose and rhamnose. Oat and barley contain gums, but are not practical for use in the present application because of the low percentage of active gum per weight volume. Most of the gums in the present application are effective at much lower dosages. Suitable gums include, inter alia, besides guar gum, the following: locust bean gum, acacia gum, gum arabic, xanthan gum, carrageenan gum, karaya gum, tragacanth gum, and ghatti gum.
Pectin substances or pectins are mixtures of polysaccharides of partially methylated and 1,4-D galacturonic acid units with side chains containing arabinose, galactose, xylose, and rhamnose. They are contained in many fruits and vegetables as well as other plants.
Other suitable gel-forming dietary fibers include psyllium husks, algal polysaccharides, glucomannan, and agar, to name a few. Lignin is a non-carbohydrate polymer of aromatic plant alcohols comprising oxygenated phenylpropane units. As a plant matures, more lignin is produced, which acts as a sort of cement as it hardens and holds together other plant cell wall constituents. Lignin passes through the digestive tract with very little change.
As already mentioned, a recent review of dietary fiber which mentions these substances is contained in the following reference: Dietary Fiber and Health, JAMA 262: No. 4, 542-546 (1989), from the Council on Scientific Affairs, American Medical Association.
Some gel-forming fibers such as guar gum are used as binders and disintegrators for compressed tablets, but at fairly low levels. At higher levels, these gel-forming fibers and gums are known not to dissolve properly when compressed into tablets.
Various unsuccessful attempts have been made to solve the problem of improper and incomplete dissolution of guar gum tablets. EPA 0080673 describes these problems in detail, and discloses the use of 5 to 30% of highly-dispersed silica gel in guar tablets. Normally used tablet disintegrants or additives such as polyvinylpyrrolidone (crosslinking agent), sodium carboxymethyl-starch, cornstarch, microcrystalline cellulose, and so on, do not lead to satisfactory results. Hard tablets are produced which do not swell properly, and which form an impenetrable layer of gel around a powder core which may pass through the gastrointestinal tract undissolved.
U.S. Pat. No. 4,824,672 describes the use of mineral carbonates to enhance dispersion of gel-forming dietary fibers in orally-administrable pharmaceutical compositions for use in reducing serum cholesterol levels. Such compositions have proved to be very effective in use for their intended purpose, but do not provide a satisfactory matrix for providing a prolonged-release unit dosage formulation of a biologically-absorbable therapeutic agent or drug.
The foregoing EPA 00808673 mentions the employment of citric acid with guar gum tablets. The citric acid and sweeteners were used, according to that disclosure, to improve the acceptability of the tablets if they were to be chewed. Accordingly, the citric acid was there used only to provide flavor and an aromatic quality to the product.
It is apparent that the prior art has not provided such formulations did not contain any mineral carbonate or bicarbonate and, moreover, when a carboxylic acid such as citric acid was employed in the compositions of that invention, "the acid is coated with 1 to 20% of a water-repellent agent based on the weight of the acid", reportedly to provide increased storage stability of the product.
It is apparent that the prior art has not provided any suitable prolonged-release unit dosage formulation for the prolonged release of an effective dose of a biologically-absorbable therapeutic agent or drug, much less such a prolonged-release unit dosage formulation which employs or embodies a gel-forming dietary fiber as an essential part of the matrix, fundamentally because of the fact that the swelling and balling and plug formation of such gel-forming dietary fibers has heretofore been considered an insurmountable disadvantage, insofar as the acid of the stomach does not readily or uniformly dissolve dietary fiber formulations, especially when in unit dosage form such as a tablet, granule, capsule, lozenge, or the like, for which reason release of any therapeutic agent or drug which may have been combined therewith was unpredict-able and non-uniform and generally insufficiently rapid to cause or permit release of all of the drug or other therapeutic agent content thereof while the unit dosage formulation was present in the gastrointestinal tract.
According to the present invention, however, excellent prolonged-release unit dosage formulations are provided, which consist essentially of an effective dose of the selected biologically-absorbable therapeutic agent or drug, a gel-forming dietary fiber, and optionally a physiologically-acceptable edible acid, preferably a food-grade organic acid or phosphoric acid, and a mineral salt which releases a physiologically-acceptable gas upon ingestion, preferably a mineral carbonate or bicarbonate which releases carbon dioxide upon ingestion. The physiologically-acceptable acid is not necessary to carry out the present invention, although it can be present to assist in providing an improved hydration rate and help to open up the tablet or other selected oral unit-dosage form involved when a quicker release of the drug is desired. According to the invention, when a biological liquid, such as stomach acid, begins to penetrate or wick into the prolonged-release unit dosage formulation, it dissolves mineral salt present therein, which reacts to cause a rapid evolution of gas, e.g., carbon dioxide. This rapid evolution of gas breaks up the prolonged-release unit dosage form, e.g., tablet, granule, capsule, lozenge, or the like, before a surface layer of gel can form around the unit dosage form, especially a tablet, from the normal reaction of the gel-forming dietary fiber, which surface layer of gel would seal the unit dosage form off from further hydration and disintegration. In another embodiment of the present invention, it may be necessary to have a physiologically-acceptable edible acid with the mineral salt to release a physiologically-acceptable gas upon ingestion. The acid would be located inside the tablet, granule, capsule, lozenge, or the like, or dispersed throughout the tablet granule, capsule, lozenge, or other unit dosage form, to increase the speed of hydration of the drug or other therapeutic agent contained in the unit dosage formulation.
According to the invention, the gel produced by the gel-forming dietary fiber modulates the release of the drug, but does not prevent the drug from being biologically absorbed, inhibition of disintegration by formation of a gel coating around the unit dosage formulation by the gel-forming dietary fiber being prevented by the evolution of a physiologically acceptable gas by virtue of the action of the mineral salt within the unit dosage formulation upon contact with biological fluids, e.g., those of the gastrointestinal tract.
It is an object of the invention to provide novel and advantageous prolonged-release unit dosage formulation and a method for prolonging the release of a drug or other active therapeutic agent upon administration to a human being involving the employment of such improved and advantageous prolonged release unit dosage formulation of the invention. Another object of the invention is to provide such formulation and method which involve the employment of a prolonged-release unit dosage formulation consisting essentially of an effective dose of a biologically-absorbable drug or other therapeutic agent, a gel-forming dietary fiber, and a mineral salt which releases a physiologically- acceptable gas upon ingestion. A further object of the invention is to optionally provide the above composition along with a physiologically acceptable acid. A further object of the invention is the provision of such formulation and method wherein the disadvantageous characteristics of the gel-forming dietary fiber matrix are offset by the inclusion of a mineral salt which releases a physiologically-acceptable gas upon ingestion, preferably a mineral carbonate or bicarbonate which releases carbon dioxide upon ingestion and to optionally include a physiologically-acceptable acid to facilitate the release of the gas. Still an additional object is the provision of such a formulation and method wherein the unit dosage formulation also contains a soluble sugar, which greatly enhances the controllable disintegration of the unit dosage formulation upon ingestion in addition to providing a more generally acceptable flavor. Still other objects will be apparent to one skilled in the art and additional objects will become obvious as this specification proceeds.